Cognitive behavioral therapy for anxiety and depression in cancer survivors: a meta-analysis

This study aimed to investigate the effects of cognitive behavioral therapy (CBT) on anxiety and depression in cancer survivors. The PubMed, Embase, PsycINFO, and Cochrane Library databases were searched. Randomized controlled trials that evaluated the effects of CBT in cancer survivors were included. The standardized mean difference (SMD) was used as an effect size indicator. Fifteen studies were included. For the depression score, the pooled results of the random effects model were as follows: pre-treatment versus post-treatment, SMD (95% confidence interval [CI]) = 0.88 (0.46, 1.29), P < 0.001; pre-treatment versus 3-month follow-up, 0.83 (0.09, 1.76), P = 0.08; pre-treatment versus 6-month follow-up, 0.92 (0.27, 1.58), P = 0.006; and pre-treatment versus 12-month follow-up, 0.21 (− 0.28, 0.70), P = 0.40. For the anxiety score, the pooled results of the random effects model were as follows: pre-treatment versus post-treatment, 0.97 (0.58, 1.36), P < 0.001; pre-treatment versus 3-month follow-up, 1.45 (− 0.82, 3.72), P = 0.21; and pre-treatment versus 6-month follow-up, 1.00 (0.17, 1.83), P = 0.02). The pooled result of the fixed effects model for the comparison between pre-treatment and the 12-month follow-up was 0.10 (− 0.16, 0.35; P = 0.45). The subgroup analysis revealed that the geographical location, treatment time and treatment form were not sources of significant heterogeneity. CBT significantly improved the depression and anxiety scores of the cancer survivors; such improvement was maintained until the 6-month follow-up. These findings support recommendations for the use of CBT in survivors of cancer.


Methods
The meta-analysis procedure was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement guidelines 30 . As this study analyzed data from previously published studies, ethical ratification was not required. Considering that this study is a meta-analysis study using the existing peer-reviewed literature,and no human/animal patients were directly involved in the study, receiving their con-sent to participate or consent to publish was not considered as necessary.
Search strategy. According to the predefined search strategy, we identified appropriate literature using the following electronic databases: PubMed, PsycINFO, Embase, and Cochrane Library. The search keywords included "cognitive behavioral therapy, " "cognitive behavior therapy, " "neoplasms, " "cancer, " "anxiety, " and "depression. " Keywords in the same category were combined with "OR" and those in different categories with "AND. " Subject terms and free words were searched in combination, and the retrieval method was adjusted according to database characteristics. The retrieval steps for the PubMed database are presented in Supplementary table 1. We focused on articles published up to May 23, 2022, without language restrictions. Additionally, the references of relevant reviews and the included literature were searched for eligible studies.
Inclusion and exclusion criteria for study selection. The inclusion criteria for the studies were as follows: (1) participant: cancer survivors (patients with cancer who had completed treatment, except for targeted treatments or hormonal treatments); (2) variable compared: differences in the effects of CBT and treatment as usual (TAU) on depression and anxiety in patients with cancer; and (3) study type: RCT.
The exclusion criteria were as follows: (1) non-literary research, such as review and meeting abstracts; (2) third-generation CBT, such as mindfulness-based cognitive therapy and acceptance and commitment therapy; (3) patients receiving or preparing to receive standard treatments, such as surgery, radiation, chemotherapy, or immunotherapy; and (4) repeated publications or multiple articles with the same data (only the article with the most complete research information was retained).
Data extraction and quality assessment. Two reviewers independently completed literature screening. After obtainment of the included literature, information on the first author, publication year, country, basic participant characteristics (sample size, sex, and age), cancer type and stage, follow-up time, intervention period, and study outcome was independently extracted according to the pre-designed table. After the data extraction, the two reviewers exchanged the tables, and disagreements were resolved via discussion. The quality of the RCTs was assessed using the Cochrane Collaboration's tool 31 . Statistical analysis. The standardized mean difference (SMD) and 95% confidence interval (CI) were used as the effect size indicators to evaluate the differences in the anxiety and depression scores between posttreatment and the 3/6/12-month follow-up. Cochran's Q test and I 2 test were used for heterogeneity testing 32 . P < 0.05 or I 2 > 50% indicated significant heterogeneity, and the random effects model was used for the data analysis. Random-effects model attempted to generalize findings beyond the included studies by assuming that www.nature.com/scientificreports/ the selected studies are random samples from a larger population 33 . P ≥ 0.05 or I 2 ≤ 50% indicated non-significant heterogeneity, and the fixed effects model was applied for the meta-analysis. Fixed-effect models assume that the population effect sizes are the same for all studies 33 . Subgroup analysis was performed according to the geographical location and treatment time. The effect of a single study on the meta-analysis was evaluated using a one-by-one exclusion method 34 . Publication bias was evaluated using the Egger test 35 . When significant publication bias existed, the stability of the combined results was assessed using the trim-and-fill method 36 . All statistical analyses were performed using the Stata 12.0 and RevMan 5.3 software.

Results
Literature search. The literature retrieval results and screening processes are presented in Fig. 1. A total of 2992 articles were retrieved from the electronic databases (1019 from PubMed, 1024 from Embase, 511 from the Cochrane Library, and 438 from PsycINFO) in this meta-analysis. After duplicate elimination, 2059 articles remained. Thereafter, 2012 articles were further removed by browsing the titles and abstracts. Finally, 15 articles were included after full-text reading, including 13 quantitative analyses 37-49 and 2 qualitative analyses.   39,46,48,52,53 , one on patients with laryngeal squamous cell carcinoma 49 and one on patients with head and neck cancer 54 . The average age of the participants ranged from 37.45 to 59.7 years. The CBT intervention period was 2-12 weeks, and the follow-up period was within 12 months after the intervention. The rating scales used for anxiety and depression are listed in Table 1.
The methodological quality assessment results of the included articles are shown in Supplementary Fig. 1A and B. Bias mainly included performance and detection biases. The bias level of the included studies was uncertain, and the methodological quality was moderate.
For the anxiety score, the change values between CBT and TAU in the comparisons of pre-treatment with post-treatment, pre-treatment with the 3-month follow-up, and pre-treatment with the 6-month follow-up showed significant heterogeneity among the included articles (I 2 > 50%, P < 0.05). The pooled results of the random effect models were as follows: pre-treatment versus post-treatment, SMD (95% CI) = 0.97 (0.58, 1.36), P < 0.0001 (  Fig. 3B). The pooled results of group therapy and individual therapy were statistically significant (P < 0.05, Supplementary Fig. 3). In addition, the subgroup analysis showed that the geographical location, treatment time and treatment form were not sources of significant heterogeneity.

Sensitivity analysis and publication bias test.
Only two studies reported the anxiety scores at the 3-month follow-up and depression and anxiety scores at the 12-month follow-up, making them unsuitable for the sensitivity analysis or publication bias test. The analysis results for the depression and anxiety scores at the other time points are summarized in Table 3. The sensitivity analysis revealed that the intervention effect of CBT was stable at post-treatment, the 3-month follow-up, and the 6-month follow-up. The Egger test was used to evaluate the publication bias between the studies ( Table 3). The included studies that investigated depression and anxiety after follow-up had a significant publication bias (P < 0.05). However, the results of the trim-and-fill method suggested that the program did not fill in the fictitious negative results to  www.nature.com/scientificreports/ enhance the symmetry of the funnel plot; further, the meta-analysis results did not change, indicating that the original pooled results were stable. The included studies that investigated the other outcome indicators did not have a significant publication bias (P > 0.05).
Qualitative analysis. Duffy et al. 54 reported differences in the depression rates between patients with cancer who underwent CBT and TAU at the 6-month follow-up, with the rate in the CBT group decreasing from 68 to 21% and that in the TAU group from 70 to 24%, showing no significant difference between the two groups (P > 0.05). Savard et al. 51 suggested that CBT significantly influenced the depression and anxiety scores at the end of the intervention (P < 0.05).

Discussion
This study analyzed the efficacy of CBT for anxiety and depression across 15 RCTs that included 1979 cancer survivors. The analysis showed that CBT can significantly reduce depression and anxiety in cancer survivors during the intervention period and until 6 months of follow-up, as measured by the depression and anxiety scores, when compared with TAU. The observed effects persisted until the 6-month follow-up, suggesting that CBT provided significant, lasting improvements in depression and anxiety. However, more high-quality RCTs are required to confirm these findings. Additionally, there was no finding that the geographical location, treatment time and treatment form of the included studies affected the heterogeneity. In a previous meta-analysis and systematic review, with pooled samples of approximately 50,000 long-term cancer survivors, the prevalence of depression and anxiety was 12% and 18%, respectively 16 . Although antidepressants are effective for the treatment of anxiety and depression, they yield poor tolerance, rebound insomnia, and adverse side effects after discontinuation 55 . Given the effects of depression and anxiety on symptom burden and www.nature.com/scientificreports/ quality of life, evidence supporting effective interventions with minimal side effects and long-term benefits is needed for cancer survivors with anxiety and depression. Evidence from RCTs has indicated that several behavioral approaches, such as mindfulness-based approaches, hypnosis, and self-management strategies, are effective in improving anxiety and depression in cancer survivors [56][57][58] . However, most studies have been conducted in breast cancer survivors; thus, these interventions need to be further tested in different groups of survivors. CBT has been demonstrated to be effective in the treatment of depression and anxiety, with well-maintained effects over a 3-month follow-up period 59 . Currently, CBT is recommended as the first-line treatment for depression and anxiety by the National Institute for Health and Care Excellence in the United Kingdom. However, among cancer survivors, the majority of CBT-related studies have focused on those with insomnia 60,61 , with less attention paid to those with depression and anxiety. A recent meta-analysis examined the effect of CBT on the quality of life and psychological health (depression, anxiety, and stress) of patients and survivors of breast cancer. It revealed that CBT is effective in improving the psychological symptoms of both patients and survivors, with meaningful clinical effect sizes 62 . In our study, the beneficial effects of CBT on depression and anxiety in the cancer survivors were maintained until the 6-month follow-up, which suggests the durability of this treatment. Our results are consistent with a previous finding that "individual CBT has short-term effects (< 8 months)" on both depression and anxiety among cancer survivors 63 . Therefore, further research is needed before CBT can be used in the long-term.
It's worth noting that, among the included literatures, several studies were based on internet CBT 39,41,48 . Traditional CBT usually proceeds through face-to-face sessions with a professional in an individual or smallgroup format and therefore requires significant manpower, time, and cost 64,65 . Internet-based CBT programs is a promising therapeutic alternative that can spread widely within a very short period. They are more accessible www.nature.com/scientificreports/ and effective than traditional face-to-face interventions in terms of manpower and cost 66 . Internet CBT may provide access to standardized, evidence-based therapy without physical and/or geographical barriers 67 . It has been reported that internet CBT can achieve comparable outcomes to face-to-face CBT for mild to severe anxiety and depression in the general population 68 . Therefore, internet CBT has potential to revolutionize the delivery of CBT, improving the accessibility and availability of CBT content for cancer survivors. The methodological quality of the included articles herein was moderate; thus, the findings may have the potential to serve as a basis for clinical practice guidelines 69 . Although we applied strict inclusion and exclusion criteria to minimize heterogeneity, there were still high levels of heterogeneity found, which may be attributed to the different methods used to deliver CBT. A subgroup analysis was then used to analyze the potential sources of heterogeneity. The analysis revealed that the geographical location and treatment time were not sources of significant heterogeneity. Importantly, a treatment time of more than 6 weeks was associated with the treatment  www.nature.com/scientificreports/ effect of CBT on both depression and anxiety. Thus, a treatment time of more than 6 weeks is recommended to ensure the efficacy of CBT. Specifically, the subgroup analysis was only performed on the post-treatment changes, since there were fewer than five included studies that conducted 3-, 6-, and 12-month follow-ups. Therefore, the effects of follow-up deserve further attention. Taken together, these findings support recommendations for the use of CBT in survivors of cancer.

Study strengths and limitations.
This study has several strengths. A wide range of databases were searched without restrictions on time scales or language. Strict inclusion and exclusion criteria were used to minimize heterogeneity. The high level of heterogeneity may be attributed to the differences in how CBT was delivered. Study selection and quality assessment were independently completed by two reviewers. The control group was limited to TAU, which can objectively evaluate the intervention effect of CBT. Additionally, the methodological quality of the included studies was moderate, and the control of selection bias, reporting bias, and loss-to-follow-up bias was reasonable. Importantly, although there was significant publication bias for some outcome indicators, the results of both the trim-and-fill method and the one-by-one elimination method suggested the high stability of the pooled results. This study has some limitations, which might have influenced the results. First, the heterogeneity of the included studies was large, and no significant source of heterogeneity was found in the subgroup analysis. Second, the CBT intervention approaches were inconsistent among the included studies, which is an important source of clinical heterogeneity. Currently, there is no appropriate quantitative method to evaluate the impact on the results of the meta-analysis. Finally, for some outcome indicators, the number of included studies was small, and the sensitivity analysis results were unstable, requiring more large-sample studies to verify the results.
Clinical implications. Depression and anxiety are highly prevalent concern, affecting cancer survivors and patients. A suite of interventions incorporating cognitive, behavioral, and educational components has been developed for depression and other psychological symptoms 70 . It has been suggested that behavioral interventions are valid for quality of life in cancer patients, and CBT is moderately efficacious for anxiety, depression, and stress symptoms 71,72 . Our study described a statistically significant effect of CBT on depression and distress among cancer survivors, and the results concluded that CBT was an effective intervention in improving depression and distress in cancer survivors during the intervention period and until 6 months of follow-up. Current interventions are often face to face and specialist led. The present mata-analysis included several studies based on internet CBT 39,41,48 , which has potential to revolutionize the delivery of CBT, improving the accessibility and availability of CBT content for cancer survivors. For future studies, it is necessary to address whether intervention effects appear after a continuous intervention.

Conclusions
This systematic review provided a detailed summary of the evidence on the effect of CBT interventions on depression and anxiety among cancer survivors and evaluated dynamic data at 3-12 months of follow-up. Compared with TAU, CBT significantly improved the depression and anxiety scores of the cancer survivors, and this improvement was maintained until the 6-month follow-up. It is recommended that more large-sample, high-quality RCTs be conducted for verification.

Data availability
All data generated or analyzed in this study are included in this published article and its supplementary information files. www.nature.com/scientificreports/